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Updated: May 1, 2026

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Kupffer cell calibration of T cell responses via VSIG4-CD5 interaction promotes tumor evasion

Xia Zhou1, Wei Liu1, Jing Hu1

  • 1National Key Laboratory of Immune Response and Immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Nature Immunology
|April 29, 2026
PubMed

Insights

VSIG4, an immune checkpoint molecule, dictates liver metastasis growth by modulating T cell responses. Blocking VSIG4 enhances anti-PD-L1 therapy efficacy, offering a new strategy for treating liver cancer.

Area of Science:

  • Immunology
  • Oncology
  • Cell Biology

Background:

  • Liver metastases often resist T cell immunotherapies due to reduced tumor immunogenicity.
  • Immune checkpoint molecules play a critical role in regulating anti-tumor immune responses.

Purpose of the Study:

  • To investigate the role of VSIG4 in liver metastasis growth and T cell modulation.
  • To explore the therapeutic potential of targeting the VSIG4-CD5 interaction in liver cancer.

Main Methods:

  • Analysis of VSIG4 expression in Kupffer cells and its interaction with CD5 on T cells.
  • Assessment of T cell receptor signaling modulation by VSIG4-CD5 engagement.
  • Evaluation of VSIG4 blockade combined with anti-PD-L1 therapy in mouse models of liver metastasis.

Main Results:

  • VSIG4-CD5 interaction impedes low-affinity CD8+ T cell activation but enhances high-affinity CD8+ T cell survival.
  • This bidirectional regulation promotes the growth of poorly immunogenic liver tumors.
  • Blocking VSIG4-CD5 interaction synergizes with anti-PD-L1 therapy to reduce liver metastasis in mice.

Conclusions:

  • VSIG4 acts as a key regulator of the liver immune microenvironment during metastasis.
  • Targeting the VSIG4-CD5 axis presents a promising strategy for overcoming immunotherapy resistance in liver cancer.
  • This study provides mechanistic insights into cancer immunoediting and potential treatments for immunologically cold tumors.

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